Two biologic abnormalities reported during depression are excess production of cortisol and decreased latency to rapid-eye-movement (REM) sleep. We have attempted to provoke similar abnormalities in well state patients off medications. The muscarinic cholinergic agonist arecoline has been used to induce REM in sleeping subjects. Our replication study has been completed and initial data analysis does not show a significant difference between 18 euthymic bipolar patients and 18 controls. The serotonin precursor tryptophan and the opiate antagonist naloxone have been used to probe cortisol secretion. Dose-response studies have been completed. Both agents provoke significant increases in cortisol. Euthymic bipolar patient-control comparison of tryptophan responses do not show supersensitivity in patients. The serotonin receptor blocker metergoline does not block the dextroamphetamine-induced rise in cortisol, although preliminary data did suggest this. A reanalysis of thymoxamine blockade of amphetamine suggests a possible role for alpha receptors in the cortisol response, at least in males. Other Challenges: The calcium channel blocker diltiazem has been tested in 12 infusions to 7 persons in an ongoing study. Thirteen persons have received ACTH infusions as part of a study of steroid effects. Twelve persons have completed a study of clonidine effects on growth hormone.